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Masha M Rosenberg, Alfred G Redfield, Mary Roberts, Lizbeth Hedstrom
The ability of enzymes to modulate the dynamics of bound substrates and cofactors is a critical feature of catalysis, but the role of dynamics has largely been approached from the perspective of the protein. Here we use an underappreciated NMR technique, subtesla high resolution field cycling31 P NMR relaxometry, to interrogate the dynamics of enzyme bound substrates and cofactors in guanosine-5'-monophosphate reductase (GMPR). These experiments reveal distinct binding modes and dynamic profiles associated with the31 P nuclei in the Michaelis complexes for the deamination and hydride transfer steps of the catalytic cycle...
March 16, 2018: Biochemistry
Magdalena Kolasa, Joanna Solich, Agata Faron-Górecka, Dariusz Żurawek, Paulina Pabian, Sylwia Łukasiewicz, Maciej Kuśmider, Kinga Szafran-Pilch, Marta Szlachta, Marta Dziedzicka-Wasylewska
Recently, it has been shown that serotonin 5-HT1A receptor interacts with dopamine D2 receptor in vitro. However, the existence of 5-HT1A -D2 heteromers in native tissue remains unexplored. In the present study, we investigated 5-HT1A -D2 receptor heteromerization in mice treated acutely or chronically with paroxetine (10 mg/kg) or risperidone (0.05 mg/kg). Receptor heteromerization was visualized and quantified in the mouse brain by in situ proximity ligation assay (PLA). Additionally, we aimed to determine the cellular localization of 5-HT1A -D2 receptor heteromers in mouse adult primary neuronal cells by immunofluorescent staining with markers for astrocytes (GFAP) and neurons (NeuN and MAP2)...
March 12, 2018: Neuroscience
Heike Bittersohl, Björn Schniedewind, Uwe Christians, Peter B Luppa
Therapeutic drug monitoring (TDM) of the immunosuppressive drug tacrolimus is essential to avoid side effects and rejection of the allograft after transplantation. In the blood circulation, tacrolimus is largely located inside erythrocytes or bound to plasma proteins and less than 0.1% is protein-unbound (free). One basic principle of clinical pharmacology is that only free drug is pharmacologically active and monitoring this portion has the potential to better reflect the drug effect than conventional measurements of total tacrolimus in whole blood...
March 7, 2018: Journal of Chromatography. A
Ioannis Lilis, Ioanna Giopanou, Helen Papadaki, Kostis Gyftopoulos
BACKGROUND: Mammalian target of rapamycin (mTOR) is a central regulator of major cellular processes such as growth and proliferation. Deregulated mTOR signaling is implicated in a wide spectrum of human malignancies including prostate cancer. The aim of this study is to address the role of phosphorylated mTOR (p-mTOR) in prostate adenocarcinoma-induced lymphangiogenesis and lymph node metastasis as well as to investigate its relationship with chicken ovalbumin upstream promoter transcriptional factor 2 (COUP-TFII) and the vascular endothelial growth factors A/C (VEGF A/C)...
March 12, 2018: Urologic Oncology
Masahiko Machida, Koichiro Kato, Motoyuki Shiga
The isotopologs of liquid water, H2 O, D2 O, and T2 O, are studied systematically by first principles PIMD simulations, in which the whole entity of the electrons and nuclei are treated quantum mechanically. The simulation results are in reasonable agreement with available experimental data on isotope effects, in particular, on the peak shift in the radial distributions of H2 O and D2 O and the shift in the evaporation energies. It is found that, due to differences in nuclear quantum effects, the H atoms in the OH bonds more easily access the dissociative region up to the hydrogen bond center than the D (T) atoms in the OD (OT) bonds...
March 14, 2018: Journal of Chemical Physics
Ankit Raj, Hiro-O Hamaguchi, Henryk A Witek
We report an exhaustive compilation of wavelength-dependent matrix elements over the mean polarizability (α¯) and polarizability anisotropy (γ) operators for the rovibrational states of the H2 , HD, and D2 molecules together with an accompanying computer program for their evaluation. The matrix elements can be readily evaluated using the provided codes for rovibrational states with J = 0-15 and v = 0-4 and for any laser wavelengths in the interval 182.25-1320.6 nm corresponding to popular, commercially available lasers...
March 14, 2018: Journal of Chemical Physics
Pushp Bajaj, Xiao-Gang Wang, Tucker Carrington, Francesco Paesani
Full-dimensional vibrational spectra are calculated for both X- (H2 O) and X- (D2 O) dimers (X = F, Cl, Br, I) at the quantum-mechanical level. The calculations are carried out on two sets of recently developed potential energy functions (PEFs), namely, Thole-type model energy (TTM-nrg) and many-body energy (MB-nrg), using the symmetry-adapted Lanczos algorithm with a product basis set including all six vibrational coordinates. Although both TTM-nrg and MB-nrg PEFs are derived from coupled-cluster single double triple-F12 data obtained in the complete basis set limit, they differ in how many-body effects are represented at short range...
March 14, 2018: Journal of Chemical Physics
E Curotto, M Mella
We have computed ground state energies and analyzed radial distributions for several gas phase and adsorbed D2 (H2 )n and HD(H2 )n clusters. An external model potential designed to mimic ionic adsorption sites inside porous materials is used [M. Mella and E. Curotto, J. Phys. Chem. A 121, 5005 (2017)]. The isotopic substitution lowers the ground state energies by the expected amount based on the mass differences when these are compared with the energies of the pure clusters in the gas phase. A similar impact is found for adsorbed aggregates...
March 14, 2018: Journal of Chemical Physics
Yexin Feng, Zhichang Wang, Jing Guo, Ji Chen, En-Ge Wang, Ying Jiang, Xin-Zheng Li
Proton tunneling is an elementary process in the dynamics of hydrogen-bonded systems. Collective tunneling is known to exist for a long time. Atomistic investigations of this mechanism in realistic systems, however, are scarce. Using a combination of ab initio theoretical and high-resolution experimental methods, we investigate the role played by the protons on the chirality switching of a water tetramer on NaCl(001). Our scanning tunneling spectroscopies show that partial deuteration of the H2 O tetramer with only one D2 O leads to a significant suppression of the chirality switching rate at a cryogenic temperature (T), indicating that the chirality switches by tunneling in a concerted manner...
March 14, 2018: Journal of Chemical Physics
Laura J Mosher, Sean C Godar, Marc Morissette, Kenneth M McFarlin, Simona Scheggi, Carla Gambarana, Stephen C Fowler, Thérèse Di Paolo, Marco Bortolato
The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates. While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses...
February 16, 2018: Psychoneuroendocrinology
Peter Kranke, Sergio D Bergese, Harold S Minkowitz, Timothy I Melson, David G Leiman, Keith A Candiotti, Ngai Liu, Leopold Eberhart, Ashraf S Habib, Jan Wallenborn, Anthony L Kovac, Pierre Diemunsch, Gabriel Fox, Tong J Gan
BACKGROUND: Postoperative nausea and vomiting causes distress for patients and can prolong care requirements. Consensus guidelines recommend use of multiple antiemetics from different mechanistic classes as prophylaxis in patients at high risk of postoperative nausea and vomiting. The prophylactic efficacy of the dopamine D2/D3 antagonist amisulpride in combination with other antiemetics was investigated. METHODS: This double-blind, randomized, placebo-controlled, international, multicenter trial was conducted in 1,147 adult surgical patients having three or four postoperative nausea and vomiting risk factors...
March 15, 2018: Anesthesiology
Adam J Stark, Christopher T Smith, Kalen J Petersen, Paula Trujillo, Nelleke C van Wouwe, Manus J Donahue, Robert M Kessler, Ariel Y Deutch, David H Zald, Daniel O Claassen
Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited...
2018: NeuroImage: Clinical
Pablo Garrido-Gil, Antonio Dominguez-Meijide, Rosario Moratalla, Maria J Guerra, Jose L Labandeira-Garcia
Gastrointestinal dysfunction is a common problem in the elderly. Aging-related changes in interactions between local dopaminergic and renin-angiotensin systems (RAS) have been observed in the brain, renal and vascular tissues. However, it is not known if these interactions also occur in the gut, and are dysregulated with aging. We showed a mutual regulation between the colonic dopaminergic system and RAS using young and aged mice deficient for major angiotensin and dopamine receptors. Aged rats showed a marked decrease in colonic dopamine D2 receptor expression, together with an increase in angiotensin type 1 (AT1) receptor expression, a decrease in angiotensin type 2 (AT2) receptor expression (i...
February 16, 2018: Oncotarget
Shih-Jeng Huang, Fu-Kuei Huang, Yu-Shan Li, Shu-Yao Tsai
Cordyceps militaris , a medicinal and edible mushroom, was used to ferment buckwheat and embryo rice by solid-state fermentation (SSF). Our aim was to investigate the effect of ultraviolet B (UVB) light irradiation on the content of vitamin D2 and biologically effective components, and antioxidant properties of buckwheat and embryo rice in SSF with C. militaris . Irradiated samples of buckwheat and embryo rice fermented by C. militaris had significantly increased vitamin D2 content, from 0-0.3 to 1.18-16.79 μg/g, while the increase in fresh embryo rice fermented by C...
December 2017: Food Technology and Biotechnology
Eduardo F Gallo, Jozsef Meszaros, Jeremy D Sherman, Muhammad O Chohan, Eric Teboul, Claire S Choi, Holly Moore, Jonathan A Javitch, Christoph Kellendonk
Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons...
March 14, 2018: Nature Communications
Mariusz Papp, Piotr Gruca, Magdalena Lason-Tyburkiewicz, Ewa Litwa, Monika Niemczyk, Katarzyna Tota-Glowczyk, Agata Faron-Gorecka, Maciej Kusmider, Joanna Solich, Marta Szlachta, Paul Willner
We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP...
March 13, 2018: Behavioural Pharmacology
Ramin Ekhteiari Salmas, Philip Seeman, Matthias Stein, Serdar Durdagi
The active (D2HighR) and inactive (D2LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor...
March 14, 2018: Journal of Chemical Information and Modeling
Aaron M Thomas, Michael Lucas, Long Zhao, Jerid Liddiard, Ralf I Kaiser, Alexander M Mebel
The crossed molecular beams technique was utilized to explore the formation of three isomers of resonantly stabilized (C5 H3 ) radicals along with their d2 -substituted counterparts via the bimolecular reactions of singlet/triplet dicarbon [C2 (X1 Σ/a3 Πu )] with methylacetylene [CH3 CCH(X1 A1 )], d3 -methylacetylene [CD3 CCH(X1 A1 )], and 1-butyne [C2 H5 CCH(X1 A')] at collision energies up to 26 kJ mol-1 via chemically activated singlet/triplet C5 H4 /C5 D3 H and C6 H6 intermediates. These studies exploit a newly developed supersonic dicarbon [C2 (X1 Σ/a3 Πu )] beam generated via photolysis of tetrachloroethylene [C2 Cl4 (X1 Ag )] by excluding interference from carbon atoms, which represent the dominating (interfering) species in ablation-based dicarbon sources...
March 14, 2018: Physical Chemistry Chemical Physics: PCCP
Naoto Takahashi, Mitsuro Kanda, Takaki Yoshikawa, Nobuhiro Takiguchi, Kazumasa Fujitani, Katsufumi Miyamoto, Yuichi Ito, Osamu Takayama, Motohiro Imano, Norio Mitsumori, Junichi Sakamoto, Satoshi Morita, Yasuhiro Kodera
BACKGROUND: Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. METHODS: A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible...
March 13, 2018: Gastric Cancer
Hiroshi Ihara, Sachiko Kiuchi, Takayuki Ishige, Motoi Nishimura, Kazuyuki Matsushita, Mamoru Satoh, Fumio Nomura, Mine Yamashita, Isamu Kitajima, Naoko Tsugawa, Toshio Okano, Kouichi Hirota, Masakazu Miura, Masayuki Totani, Naotaka Hashizume
BACKGROUND: To assess vitamin D nutritional status, serum total 25-hydroxyvitamin D [25(OH)D] concentration is measured. We used six automated 25(OH)D immunoassays (AIAs) available in Japan and certified by the Vitamin D Standardization Program (VDSP) at U.S. CDC to assess the concordance of assay results. METHODS: Serum total 25(OH)D concentrations in SRM 972a and 20 sera from patients were determined using three liquid chromatography-tandem mass spectrometry (LC-MS/MS) and six AIAs (pilot study), and an additional 110 sera were assessed by the six AIAs (surveillance study)...
January 1, 2018: Annals of Clinical Biochemistry
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